The present invention relates to pharmaceutical compositions which comprise CCL2 and methods of using same for the treatment of inflammation such as associated with allergy and autoimmune diseases.
While the invention will be described herein in more detail with respect to the treatment of inflammation associated with asthma and autoimmune diseases, it is to be understood that the invention is applicable to the treatment of any medical condition associated with CCR2/CCL2 dependent cell migration.
The surveillance of the body for foreign antigens is a critical function of the immune system. An important part of antigen recognition, is the unceasing migration of B and T cells in and out of lymph nodes from the bloodstream across the specialized endothelial walls of blood vessels, located in specific areas of lymphoid organs, called high endothelial venules (HEV). This migration increases the probability of encounter between antigen and the appropriate B and T cell, an encounter essential for recognition and initiation of an immune response. For a review of homing and cellular migration in lymph nodes see von Adrian and Mempel [Nature reviews, Immunology, 3: 867-876 (2003)].
T-cells play a key role in initiating and perpetuating inflammation, via the production of soluble mediators in addition to cell/cell contact interactions with a variety of cell types through membrane receptors and their ligands. T-cell subsets express unique patterns of homing molecules to interact with organ-specific cells for preferential recruitment to distinct target tissues. Indeed, chemo-attractants and cellular activators are among others, responsible for neutrophil trafficking into inflamed tissues, as well as for lymphocyte homing into foci of chronic inflammation.
A specific malfunction of the immune system occurs when lymphocytes and eosinophils infiltrate the airway wall of the lung and eventually cause asthma. This chronic inflammatory disorder of the bronchial airways is characterized by intermittent episodes of airway obstruction and wheezing. Specific symptoms include variable airflow obstruction, airway hyper-responsiveness (AHR) and airway inflammation. Although asthma is multifactorial in origin, it has been suggested that T lymphocytes, and in particular CD4+ T cells producing a Th2 pattern of cytokines, have a prominent effect on the pathogenesis of this disease while T helper 1 cells regulate allergic airway inflammation and mucus production. [Cohn, L., et al., J. Exp. Med. 190:1309 (1999)].
Current treatments for asthma include relieving bronchodilators based on β2 adrenergic receptor agonists, which cause immediate relief of the symptoms, but do not treat the disease; and long term therapy based on anti-inflammatory treatments. Treatment of asthma, however, remains unsatisfactory in that in most cases it is life long, requiring larger or more frequent doses of medicine. This results in either abandoned or misused treatment by the subject, due to its inconvenience, or to increased side effects associated with prolonged use of the medicine, often compromising patient's life quality, as well as increasing the risk of drug resistance. Long term use of beta agonists also involves pronounced side effects, including tachycardia (rapid heartbeat), skeletal muscle tremor, hypokalemia, increased lactic acid, headache, and hyperglycemia.
Another malfunction of the immune system occurs when immune cells attack the bodies own cells and tissues resulting in an autoimmune disease, such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD, e.g. colitis). Rheumatoid arthritis is a chronic inflammatory autoimmune disease of the joints. Although the cause of RA is currently unknown, once triggered, the immune response including CD4+ and CD8+ T cells, cause inflammation of the synovium. RA is also a systemic disease affecting extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs and muscles. Currently there is no known cure for rheumatoid arthritis and the main goal of treatment is to reduce joint inflammation and pain, maximize joint function and prevent joint destruction and deformity.
IBD, mainly Crohn's disease and ulcerative colitis (UC), are autoimmune inflammatory conditions affecting the gastrointestinal tract. IBD is currently believed to be caused by activation of mucosal T lymphocytes and in particular CD4+ T cells [Neurath, AGAH 2003, 2:op019]. Current treatments of IBD include anti-inflammatory drugs and immunosuppressive drugs (including steroid based, further explained hereinbelow). However, these treatments remain unsatisfactory and IBD remains a life long disease requiring larger and sometimes frequent doses of medicine.
Anti-inflammatory drugs, for treatment of asthma in particular and autoimmune diseases in general, include steroid based medicines, taken either by inhalation or orally, both accompanied by side effects. These include hoarseness of the voice and a sore throat (usually together with fungal infection) in inhaled dosages, and more severe risks involved with long term use or oral administration, including loss of adrenal function and growth hormone production (leading among others, to growth retardation in children), increased susceptibility to infection, slow healing, salt retention (leading to leg swelling, raised blood pressure, weight increase and heart failure), tremor, increased susceptibility to eye disease, particularly glaucoma and cataract, skin thinning resulting in easy bruising (purpura), thinning of the bones (osteoporosis) and more.
Anti-inflammatory treatment with leukotriene modifiers was thought to be advantageous in that it does not involve pronounced side effects, but the efficiency of these drugs is controversial. Leukotriene modifiers block a specific part of the inflammatory cascade that typically occurs in asthma and autoimmune conditions, and is thought to be limited only to specific subsets of patients. Furthermore, like other treatments, these need to be taken as a prophylactic, and insufficient or inefficient self administration further reduces their efficiency.
Other asthma therapies are based on mast cell inhibitors like cromolyn sodium and nedocromil sodium which prevent the release of histamines. However, these drugs are not potent, do not relieve severe symptoms or symptoms which have already started, are required to be taken four times a day and start taking effect only after a period of a month.
Asthma, rheumatoid arthritis and IBD therefore remain chronic diseases which require life long treatment, accompanied with inconvenient use of drugs together with unwanted side effects.
Previous studies on inflammatory conditions, including asthma, focused on the recruitment of leukocytes to the lymph nodes (LN) or sites of inflammation. However, little is known about the molecular mechanisms that negatively control or prevent homing of cells to these sites, thereby contributing to the fine tuning of the immune response at specific lymphoid and peripheral tissues.
Recently two pathways that negatively regulate homing of B cells to the lymph nodes were characterized. It was found that immature B cells can down regulate their own integrin-mediated adhesion to the extracellular matrix and thereby suppress their migration into non-splenic sites [Flaishon, L. et al., J. Exp. Med. 192:1381(2000)]. This inhibition is mediated by two independent pathways. The first one involves the secretion of IFN-γ by immature B cells, which interacts with its receptor, and causes inhibition of cytoskeleton rearrangement, required for promoting integrin-mediated adhesion and migration of B cells. The second pathway is regulated by the chemokine receptor, CCR2. In an analysis done with mice lacking CCR2, it was found that CCR2 downregulates immature B cell homing to the lymph nodes independently of the negative regulation of IFN-γ. This was determined by the elevation of immature CCR2−/− B cells migration and cytoskeletal rearrangement as a response to SDF-1 stimulation, and by the elevation of CCR2−/− B-cell homing to the LN. CCR2 is normally expressed on murine immature B cells and its expression is downregulated following differentiation to the mature stage [Flaishon, L., et al., Blood 104:933. (2004)].
CCL2, (also called Macrophage Chemotactic Protein-1 or MCP-1) is particularly highly expressed during inflammation, and is a potent monocyte as well as a lymphocyte chemoattractant. CCL2 activates CCR2 on rolling monocytes, triggering integrin mediated arrest. CCL2 is also one of the strongest histamine inducing factors.
Most studies and medical applications of the CCL2/CCR2 interaction suggest downregulating CCL2/CCR2 functions as a possible modality for the treatment of cancer [e.g. ovarian cancer: Sica, A. et al., J. Immunology (2000) 164(2):733-8)], inflammatory diseases [e.g., human crescentic glomerulonephritis: Segerer et al. J. Am. Soc. Nephrol. 11:2231-2242 (2000)] and autoimmune reactions [e.g., the significant role CCL2 appears to play during the early stages of allergic responses because of its ability to induce mast cell activation, directly inducing AHR (airways hyper-responsiveness; Campbell et al., J Immunol 163:2160-2167 (1999)].
U.S. patent applications 20050232923, 20050058639, 20050054668, 20040138171, 20040047860, 20020106355 and 20020099054 are just a few of many examples of suggested teachings for treating various diseases by antagonizing the CCL2/CCR2 interaction. The potential therapeutic value of antagonism of the CCL2/CCR2 interaction was utilized for example in treating asthma. Sequestration of CCL2 with a neutralizing antibody in ovalbumin-challenged mice resulted in marked decrease in bronchial hyper-responsiveness and inflammation [Jose-Angel Gonzalo, et al., J. Exp. Med. 1998, 188, 157]. In another study, MCP-1−/− mice displayed a reduced response to challenge with Schistosoma mansoni egg [Bao Lu, et al., J. Exp. Med. 1998, 187, 601].
Thus, to date, treatment of inflammatory diseases by administration of CCL2 has never been suggested.
There is thus a widely recognized need for pharmaceutical compositions which comprise CCL2 and methods of using same for treating inflammation, devoid of the above limitations.